tbuckley/cabot-search huggingface dataset:
Abstract 2391: Alterations in metformin mediated metabolism in chemoresistant ovarian cancer cells
Authors: Brenita Colette Jenkins, Debarshi Roy, Kristal Maner-Smith, Viji Shridhar
Journal: Cancer Research (2022)

Abstract Ovarian cancer (OVCA) is the fifth leading cause of death in post-menopausal women in comparison to all other gynecologic malignancies. Late detection of OVCA is common as screening is done mostly in women over 63. This delay in screening coupled with poor prognosis presents the need for novel treatment measures. Repurposing of Metformin (Met), a biguanide used to increase insulin responses in the body, has been identified as a promising approach for therapeutic treatment in OVCA patients. The purpose of this study is to isolate metabolic pathways used by Met to alter OVCA onset. Preliminary results show that Met inhibits cell proliferation and clonogenic growth in both HeyA8 and HeyA8MDR which are drug-sensitive and drug-resistant cell lines, respectively. In combination with carboplatin, Met treatment enhanced chemosensitivity in both cell lines. In addition, lipidomic analysis was done to monitor the impact of lipid metabolites on OVCA cells. Our analysis showed differences in neutral lipid composition in drug-sensitive and resistant cells which indicates the role of various lipid species play in mediating drug-resistance. Furthermore, Met treatment triggered anti-cancerous pathways through syntheses of lipid metabolites. This data indicates that cell proliferation, along with clonogenic growth are inhibited dose dependently by Met treatment in drug-resistant and drug-sensitive cell lines. Chemosensitivity is enhanced by Met treatment in combination with carboplatin in HeyA8 and HeyA8MDR cell lines. Together, the data suggests that autophagy and lipid biogenesis can be altered through metabolic pathways by Met treatment. Through the use of repurposed Metformin, this approach shows promising results of a treatment regimen and potential prevention of OVCA. Citation Format: Brenita Colette Jenkins, Debarshi Roy, Kristal Maner-Smith, Viji Shridhar. Alterations in metformin mediated metabolism in chemoresistant ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2391.
Abstract 1829: Characterization of factors affecting sensitivity and resistance to PRMT5 inhibition in glioblastoma
Authors: Tsung-Lin (Gavin) Tsai
Journal: Cancer Research (2022)

Abstract BACKGROUND: Glioblastoma (GBM) is a highly infiltrative and aggressive malignancy with few treatment options; all patients develop recurrence after initial therapy. Due to the dismal outcome of these patients, identification of GBM-specific targets for therapeutic development is urgently needed. PRMT5 is a protein arginine methyltransferase that catalyzes the symmetric dimethylation of arginine residues within histones marks, resulting in chromatin restructuring, which in turn promotes oncogenic processes. PRMT5 inhibition has shown efficacy against multiple malignancies; MTAP loss has been associated with increased sensitivity to PRMT5 inhibitors. Here, we examined the effects of pharmacological abrogation of PRMT5 function using highly specific, brain penetrant, orally bioavailable inhibitors and assessed the role of MTAP and p53 expression on sensitivity to these agents. MATERIALS AND METHODS: Using pharmacological inhibition of PRMT5 using with the highly specific inhibitors PRT808 and PRT811, we examined their effects on apoptosis, cell proliferation, cell cycle distribution, and methylation markers in patient-derived glioma stem-like cells (GSC) with epigenetic and genetic signaling. Additional studies to identify transcriptomic (RNA-seq), and proteomic (RPPA) landscape related to PRMT5 in gliomas are ongoing. RESULTS: PRT808 and PRT811 induced potent reduction of symmetrical dimethylation (SDMA) protein marks in all GSC tested. However, treatment of GSC214 (mutant p53), GSC262 (mutant p53), GSC811 (truncated p53), and GSC11 (wild type p53) showed that wild type and truncated p53-expressing lines (GSC811 and GSC11) were more sensitive than GSC cell lines expressing mutant p53 (GSC214 and GSC262). There was no correlation between MTAP status and sensitivity to PRMT5 inhibition. In addition, PRMT5 inhibition resulted in reduced proliferation and alteration of several cell survival pathways; induction of apoptosis in GSC cell lines at late time points around 8-9 days after single dose treatment even though SDMA reduction occurred as early as 3 days. CONCLUSIONS: Our results demonstrate pharmacological PRMT5 inhibition induced SDMA reduction and late apoptosis in genetically and epigenetically heterogeneous patient-derived GSC lines and that mutant p53 lines are less sensitive to PRMT5 inhibition. Additional studies related to splicing defects upon PRMT5 inhibition are ongoing and will be presented at the meeting. Citation Format: Tsung-Lin (Gavin) Tsai. Characterization of factors affecting sensitivity and resistance to PRMT5 inhibition in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1829.
Abstract 3714: The antitumor activity of cannabis sativa and CBD in prostate cancer PC3 cells
Authors: Lesetja Raymond Motadi, Nonhlanhla B. Moleya
Journal: Cancer Research (2022)

Abstract Prostate cancer is the second most frequently occurring carcinoma in males worldwide and one of the leading causes of death in men around the world. Recent studies estimate that over 1.4 million males are diagnosed with prostate cancer on an annual basis, with approximately 375 000 succumbing to the disease annually. With current treatments continuing to show severe side effects, there is a need for new treatments. In this study we looked at the effect of cannabis sativa extract, cannabidiol and cisplatin on prostate cancer cells, PC3. Methods: In addressing the above questions, we employed the MTT assay to measure the antiproliferative effect on PC3 cells following treatment with varying concentrations of Cannabis sativa extract, cisplatin and cannabidiol. xCELLigence was also used to confirm the IC50 activity in which cells were grown in a 16 well plate coated with gold and monitor cell. Caspase 3/7 activity was also measured using 96 well-plate following treatment. Western-blot and qRT-PCR was also used to measure the gene expression of tumor suppressor genes, p53, Bax and Bcl2. Animal studies were employed to measure the growth of PC3-mouse derived cancer to evaluate the effect of compounds in vivo. Results: From the treatment with varying concentrations of Cannabis sativa extract, cannabidiol and cisplatin, we have observed that the three compounds induced antiproliferation of PC3 cancer cell lines through the activation of caspase 3/7 activity. We also observed induction of apoptosis in these cells following silencing of retinoblastoma binding protein 6 (RBBP6), with upregulation of p53 and bax mRNA expression, and a reduction in Bcl2 gene expression. The growth of tumors in the mouse models were reduced following treatment with cisplatin and cannabidiol. Conclusion: We demonstrated that cannabidiol is a viable therapy to treat prostate cancer cells, in combination with silencing of RBBP6. This suggests that cannabidiol rather Cannabis sativa extract may play an important role in reducing cancer progression. Citation Format: Lesetja Raymond Motadi, Nonhlanhla B. Moleya. The antitumor activity of cannabis sativa and CBD in prostate cancer PC3 cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3714.
Abstract 6284: Exosomal miR-29b derived from mesenchymal stem cell (MSC) may suppress peritoneal metastasis via the effects on peritoneal mesothelial cells
Authors: Yuki Kimura, Hideyuki Ohzawa, Yuki Kaneko, Kohei Tamura, Yurie Futoh, Kazuya Takahashi, Akira Saito, Mineyuki Tojo, Hideyo Miyato, Joji Kitayama
Journal: Cancer Research (2022)

Abstract Background: Mesothelial cells play tumor-promoting roles in the development of peritoneal metastasis (PM) through mesothelial-mesenchymal transition (MMT). We reported miR-29b suppressed MMT of human peritoneal mesothelial cell (HPMC). Methods: MiR-29b mimics and negative control miRNA (NC) were transfected to human bone marrow derived MSC by lipofection method. Exosomes were purified from the culture supernatants of the MSC with ultracentrifugation, and added to HPMC. Proliferation and migration of HPMC were examined with MTT assay and transwell assay, respectively. MMT of HPMC induced by 10 ng/ml TGF-β, and evaluated with immunofluorescence staining. Results: MSC transfected with miR-29b mimics produced significantly increased amounts of miR-29b-containing exosomes (p&amp;lt;0.0001, n=3) as compared with negative control. After 24h-culture with PKH-26 stained exosomes, HPMC actively took the exosomes. After 48 hr-culture with TGF-β, HPMC apparently changed the morphology from round to spindle shape. The expression level of E-cadherin and Calretinin in HPMC was decreased while vimentin and Fibronectin tended to be upregulated by TGF-β. However, exosomes from miR-29b transfected MSC significantly suppressed the morphological changes and reduced the expression levels of vimentin and Fibronectin with restored expression of E-cadherin and Calretinin, suggesting the inhibition of MMT in HPMC. The exosome inhibited the proliferation and migration of HPMC by 31±14% (p&amp;lt;0.01, n=5) and 67±9% (p&amp;lt;0.01, n=3), and inhibited the adhesion of NUGC by 90±3% (p&amp;lt;0.001, n=5) as compared with NC exosome. Conclusion: Exosomes from MSC transfected with miR-29b mimic efficiently suppresses MMT. Replacement of the miR-29b in peritoneal cavity might be used for the treatment of PM partially via the effects on mesothelial cell. Citation Format: Yuki Kimura, Hideyuki Ohzawa, Yuki Kaneko, Kohei Tamura, Yurie Futoh, Kazuya Takahashi, Akira Saito, Mineyuki Tojo, Hideyo Miyato, Joji Kitayama. Exosomal miR-29b derived from mesenchymal stem cell (MSC) may suppress peritoneal metastasis via the effects on peritoneal mesothelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6284.
Abstract 4185: Targeting variant of CEACAM5 and CEACAM6 using NEO-201 and IL-15 in gynecologic cancers
Authors: Maria Pia Morelli, Massimo Fantini, Kwong Y. Tsang, Phillip Arlen, Paulette Fauceglia, Lidia Hernandez, Soumya Korrapati, Elijah Edmonson, Christopher Cole, Christina M. Annunziata
Journal: Cancer Research (2022)

Abstract Background: Uterine and ovarian cancers express glycosylated forms of CEACAMs 5 and 6 that regulate interactions with the tumor microenvironment. NEO-201 is a novel monoclonal antibody that binds a glycosylated variant of these CEACAMs that is upregulated in cancer compared to normal uterine or ovarian epithelia. Previous work has shown that NEO-201 induced cancer cell death predominantly by antibody-dependent cellular cytotoxicity (ADCC) that can be enhanced by the addition of IL-15. Methods: NEO-201 target expression was assessed on uterine and ovarian cancer cell lines, as well as a tissue microarray of primary uterine cancer samples. Cell lines were profiled with DNA and RNA sequencing. Chromium-release assays were performed to quantify ADCC without and with varying concentrations of IL-15 and varying target to effector ratios. In vivomodeling was performed using ovarian cancer cell line OV90, and mice were treated with NEO-201, with PBMC or NK cells, with or without IL-15. Results: NEO-201 target antigen was highly expressed in uterine cancer cell line ACI158 and ovarian cancer cell line OV90. The antigen was expressed in primary uterine cancer samples as well. IL-15 consistently increased the in vitro killing of both cell lines and was further enhanced with the use of NK cells compared to PBMC. These findings were replicated in the in vivo mouse model, where mice survived longest with the combination of NEO-201, IL-15 and NK cells. Conclusions: The ADCC activity of NEO-201 monoclonal antibody was enhanced with the addition of IL-15, especially in the presence of purified NK cells. NEO-201 with IL-15 shows promising results as a potential treatment for biomarker-selected gynecologic cancers. Citation Format: Maria Pia Morelli, Massimo Fantini, Kwong Y. Tsang, Phillip Arlen, Paulette Fauceglia, Lidia Hernandez, Soumya Korrapati, Elijah Edmonson, Christopher Cole, Christina M. Annunziata. Targeting variant of CEACAM5 and CEACAM6 using NEO-201 and IL-15 in gynecologic cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4185.
Abstract 3885: USP7 is an interaction partner of EZHIP and potential druggable target in PFA ependymomas
Authors: Anne Jenseit, Aylin Camgöz, Monika Mauermann, Stefan M. Pfister, Marcel Kool
Journal: Cancer Research (2022)

Abstract Ependymomas (EPN) are tumors of the central nervous system (CNS) that can arise in the supratentorial brain (ST-EPN), hindbrain or posterior fossa (PF-EPN), or anywhere in the spinal cord (SP-EPN), both in children and adults. Molecular profiling has identified distinct subgroups and subtypes in each of the anatomic compartments. In the posterior fossa, three subgroups have been identified: PFA, PFB and PF-SE. Of them, PFA ependymomas are characterized by a young median age at diagnosis, an overall balanced genome and a bad clinical outcome (56% 10-year overall survival). Standard therapy consists of tumor resection and radiotherapy, but working chemo- or targeted therapies will be essential to improve patient outcomes. Recently, we and others identified enhancer of zeste inhibiting protein (EZHIP) as potential main driver of PFA tumorigenicity. By inhibiting EZH2, the catalytic subunit of the polycomb repressive complex 2 (PRC2), EZHIP prevents the distribution of the epigenetic repressor mark H3K27me3. However, since EZHIP does not possess any known enzymatic functions itself, it does not serve as the druggable target urgently needed for PFA tumors. Thus, interaction partners are one main focus of ongoing PFA research. In this project, we focused on the ubiquitin-specific protease 7 (USP7), a well-known regulator of cancer pathways with a variety of inhibitors available, which was observed to interact with EZHIP in non-PFA cell lines before. We were able to confirm this interaction of EZHIP and USP7 in PFA cells in vitro by co-immunoprecipitation and mass spectrometry, and could show that the EZHIP-USP7 interaction is independent of EZH2, a separate interactor of both. Functionally, we are testing the hypothesis that USP7 de-ubiquitinates EZHIP, thereby preventing its proteasomal degradation and thus stabilizing the protein. As EZHIP expression is essential to PFA cell survival, we aim to target EZHIP indirectly by interfering with its stability regulation via USP7. RNAi-based knockdown (KD) experiments have been used to test a susceptibility of PFA cells to a loss of USP7, focusing on effects on cell proliferation and apoptosis, but also investigating gene expression changes provoked by a change in USP7 levels. Moreover, multiple USP7 inhibitors already highly affect the survival of different PFA cell lines in vitro. Ongoing experiments with PFA patient-derived xenograft (PDX) models will hopefully confirm the strong effect of USP7 inhibitors in PFA, and help to improve targeted therapy for PFA patients. Citation Format: Anne Jenseit, Aylin Camgöz, Monika Mauermann, Stefan M. Pfister, Marcel Kool. USP7 is an interaction partner of EZHIP and potential druggable target in PFA ependymomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3885.
Abstract 1434: Molecular characteristics of breast cancer patients subjected to screening for germline predisposition in a population-based observational study
Authors: Deborah F. Nacer de Oliveira, Johan Vallon-Christersson, Hans Ehrencrona, Anders Kvist, Åke Borg, Johan Staaf
Journal: Cancer Research (2022)

Abstract An estimated 5-10% of breast cancer cases carry germline mutations in genes associated with a moderate to strong breast cancer risk, like BRCA1 and BRCA2. These mutations can influence disease onset, progression, biology of the tumor, potential for therapy, risk of recurrence and cancer risk of close relatives. This warrants clinical germline screening for such gene variants according to national guidelines on patient selection. In this study we aimed to molecularly and clinicopathologically contrast clinically screened patients and their tumors against unscreened patients. For this we used a population-based breast cancer cohort from southern Sweden with 6660 patients (14% of which had been screened) with accompanying RNA-sequencing and clinicopathological registry data. Screening subsets were analyzed within five clinically relevant breast cancer subgroups based on hormone receptor and lymph node status. Among other features, we investigated clinicopathological characteristics, risk of tumor recurrence, survival outcomes, tumor proliferation markers, immune cell content, genes differentially expressed and the pathways in which they were involved. Most differences were found in the triple negative breast cancer (TNBC) subgroup: when compared to patients that had not been screened, the screened subset contained younger individuals showing better overall survival, more proliferative tumors with upregulated genes that belong to DNA replication and double-strand break repair processes, lower proportion of M2 macrophages and higher proportion of T-helper 2 cells. As so, Swedish screening guidelines divide TNBC cases into two separate subsets possibly by selecting distinct underlying biological and mutational mechanisms associated with DNA repair deficiency (e.g., through BRCA1/2-deficiency), a disparity not seen in other breast cancer clinical subgroups. Understanding the molecular landscape of defined screening populations may improve future guideline updates, which in turn would also improve patient and resource handling. Citation Format: Deborah F. Nacer de Oliveira, Johan Vallon-Christersson, Hans Ehrencrona, Anders Kvist, Åke Borg, Johan Staaf. Molecular characteristics of breast cancer patients subjected to screening for germline predisposition in a population-based observational study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1434.
Abstract 5812: Histone deacetylase 10 supports tumor growth under polyamine-limiting conditions
Authors: Tracy Murray Stewart, Raphael R. Steimbach, Jackson R. Foley, Aubry K. Miller, Robert A. Casero
Journal: Cancer Research (2022)

Abstract Cytosolic histone deacetylase 10 (HDAC10) is specifically deacetylates the modified polyamine N8-acetylspermidine (N8-AcSpd). Although intracellular concentrations of N8-AcSpd are low, extracellular sources can be abundant, particularly in the colonic lumen. Extracellular polyamines, including those from the diet and microbiota, can support tumor growth both locally and at distant sites. However, the contribution of N8-AcSpd is unknown. We hypothesized that HDAC10, by converting N8-AcSpd to spermidine, may provide a source of this growth-supporting polyamine in circumstances of reduced polyamine biosynthesis, such as in polyamine-targeting, anticancer therapies. Inhibitors of polyamine biosynthesis, such as difluoromethylornithine (DFMO), inhibit tumor growth but with compensatory uptake of extracellular polyamines that have limited their clinical success. Combining DFMO with inhibitors of polyamine uptake have improved the antitumor response. However, acetylated polyamines may use different transport machinery than the parent molecules. The current study uses CRISPR/Cas9-mediated HDAC10-knockout cell lines and recently developed, selective HDAC10 inhibitors to investigate the contribution of HDAC10 in maintaining tumor cell proliferation. Inhibition of cell growth by DFMO-associated polyamine depletion is successfully rescued by the provision of physiological concentrations of exogenous N8-AcSpd, which is converted to spermidine and spermine, only in cell lines with HDAC10 activity. Loss of HDAC10 prevents both restoration of polyamine levels and growth rescue, implicating HDAC10 in supporting polyamine-associated tumor growth. These data suggest the utility of HDAC10-specific inhibitors as an antitumor strategy that may have particular value in improving the response to polyamine-blocking therapies. Citation Format: Tracy Murray Stewart, Raphael R. Steimbach, Jackson R. Foley, Aubry K. Miller, Robert A. Casero. Histone deacetylase 10 supports tumor growth under polyamine-limiting conditions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5812.
Abstract 5922: Clinical validation of a spectroscopic liquid biopsy for early detection of brain cancer
Authors: James M. Cameron, Paul M. Brennan, Georgios Antoniou, Holly J. Butler, Loren Christie, Justin J.A. Conn, Tom Curran, Ewan Gray, Mark G. Hegarty, Michael Jenkinson, Daniel Orringer, David S. Palmer, Alexandra Sala, Benjamin R. Smith, Matthew J. Baker
Journal: Cancer Research (2022)

Abstract Diagnostic delays impact the quality of life and survival of patients with brain tumors. Earlier and expeditious diagnoses in these patients are crucial to reducing the morbidities and mortalities associated with brain tumors. A simple, rapid blood test that can be administered easily in a primary care setting to efficiently identify symptomatic patients who are most likely to have a brain tumor would enable quicker referral to brain imaging for those who need it most. Blood serum samples from 603 patients were prospectively collected and analyzed. Patients either had non-specific symptoms that could be indicative of a brain tumor on presentation to the Emergency Department, or a new brain tumor diagnosis and referral to the neurosurgical unit, NHS Lothian, Scotland. Patient blood serum samples were analyzed using the Dxcover® Brain Cancer liquid biopsy. This technology utilizes infrared spectroscopy combined with a diagnostic algorithm to predict the presence of intracranial disease. Our liquid biopsy approach reported an area under the receiver operating characteristic curve of 0.8. The sensitivity-tuned model achieves a 96% sensitivity with 45% specificity (NPV 99.3%) and identified 100% of glioblastoma multiforme patients. When tuned for a higher specificity, the model yields sensitivity of 47% with 90% specificity (PPV 28.4%). This simple, non-invasive blood test facilitates the triage and radiographic diagnosis of brain tumor patients, while providing reassurance to healthy patients. Minimizing time to diagnosis would facilitate identification of brain tumor patients at an earlier stage, enabling more effective, less morbid surgical and adjuvant care. Citation Format: James M. Cameron, Paul M. Brennan, Georgios Antoniou, Holly J. Butler, Loren Christie, Justin J.A. Conn, Tom Curran, Ewan Gray, Mark G. Hegarty, Michael Jenkinson, Daniel Orringer, David S. Palmer, Alexandra Sala, Benjamin R. Smith, Matthew J. Baker. Clinical validation of a spectroscopic liquid biopsy for early detection of brain cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5922.